Macropinocytosis is an actin-dependent process initiated from surface membrane ruffles. In macropinocytosis, large endocytic vacuoles called macropinosomes mediate the non-selective uptake of macromolecules such as solute molecules, nutrients, and antigens. All animal cells take up extracellular fluid and substances through macropinocytosis which represents a portal of cell entry exploited by a range of pathogens.
The Filoviridae family includes highly infectious and pathogenic Ebolaviruses and Marburgviruses, and a recently identified member Lloviu. Since the first reported outbreak in 1976, each successive decade has seen an increase in recurrence of Filovirus outbreaks, incidences as well as number of infected people. Filoviridae are non-segmented, negative sense single stranded RNA viruses. Both Ebolaviruses and Marburgviruses are highly contagious and based on known outbreaks, average case fatality rates range from 42%-90%. According to WHO, the recent Ebola virus outbreak has resulted in more than 28,000 infections and more than 11,000 deaths.
Filovirus entry into cells is dependent on the single viral glycoprotein (GP). Though GPs of Ebolaviruses and Marburgviruses are quite distinct from each other, their entry mechanisms share common traits, offering potential broad-spectrum anti-Filoviral targets. Filoviral GP binds receptors; virus is internalized through macropinocytosis and trafficked through endosomes, which is dependent on the calcium channel, TPC2. During trafficking the virus is exposed to an increasingly acidic environment in which proteases are activated and cleave the GP, allowing interaction with NPC1, a key protein found in endosomes.
Several therapeutic candidates are currently undergoing clinical trials. Many of these drugs and therapies target only the current outbreak strain of Ebolavirus (previously named Zaire Ebolavirus) and closely related strains. However, there is still a need to be able to treat disease caused by other species of Ebola and Marburg viruses. Though Ebolaviruses and Marburgviruses are quite distinct from each other, they still share common traits that when inhibited by a small molecule may be useful as a broad-spectrum anti-filoviral agent.
Developing small molecules into drugs is inefficient with only 1 in 100,000 hits from a screen making it to the clinic. Large screens increase chances of eventually identifying active and specific small molecules that can be used as drugs. However, this work is hampered by the dangerous nature of Filoviruses, requiring high containment laboratories for all work. Instead, much of the recent progress in identifying anti-Filoviral compounds has been made by testing small libraries of clinically approved medications for other indications or other virus types. Identifying and developing specific and potent anti-Filoviral agents continues to be very challenging.